Honokiol induces cell cycle arrest and apoptosis via inhibition of survival signals in adult T-cell leukemia.

Abstract

BACKGROUND:

Honokiol, a naturally occurring biphenyl, possesses anti-neoplastic properties. We investigated activities of honokiol against adult T-cell leukemia (ATL) associated with human T-cell leukemia virus type 1 (HTLV-1).

METHODS:

Cell viability was assessed using colorimetric assay. Propidium iodide staining was performed to determine cell cycle phase. Apoptotic effects were evaluated by 7A6 detection and caspases activity. Expressions of cell cycle- and apoptosis-associated proteins were analyzed by Western blot. We investigated the efficacy of honokiol in mice harboring tumors of HTLV-1-infected T-cell origin.

RESULTS:

Honokiol exhibited cytotoxic activity against HTLV-1-infected T-cell lines and ATL cells. We identified two different effects of honokiol on HTLV-1-infected T-cell lines: cell cycle inhibition and induction of apoptosis. Honokiol induced G1 cell cycle arrest by reducing the expression of cyclins D1, D2, E, CDK2, CDK4, CDK6 and c-Myc, while apoptosis was induced via reduced expression of cIAP-2, XIAP and survivin. The induced apoptosis was also associated with activation of caspases-3 and -9. In addition, honokiol suppressed the phosphorylation of IκBα, IKKα, IKKβ, STAT3, STAT5 and Akt, down-regulated JunB and JunD, and inhibited DNA binding of NF-κB, AP-1, STAT3 and STAT5. These effects resulted in the inactivation of survival signals including NF-κB, AP-1, STATs and Akt. Honokiol was highly effective against ATL in mice

CONCLUSIONS:

Our data suggested that honokiol is a systemically available, non-toxic inhibitor of ATL cell growth that should be examined for potential clinical application.

GENERAL SIGNIFICANCE:

Our findings provide a rationale for clinical evaluation of honokiol for the management of ATL.

• Authors: Chie Ishikawa, Jack L Arbiser, Naoki Mori
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1820 Issue 7 Pg. 879-87 (Jul 2012) ISSN: 0006-3002 [Print] Netherlands
• PMID: 22465179 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Biphenyl Compounds
• Lignans
• NF-kappa B
• honokiol

Topics

• Adult
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Biphenyl Compounds (pharmacology)
• Blotting, Western
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Electrophoretic Mobility Shift Assay
• Female
• Humans
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, metabolism, pathology)
• Lignans (pharmacology)
• Mice
• Mice, Inbred ICR
• Mice, SCID
• NF-kappa B (genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured